Preparation of norlabdane oxide

ABSTRACT

Norlabdane oxide, which is a well known fragrance material having ambergris-type odors, is prepared from 12-acetoxy-norlabdane oxide by a hydrogenation reaction.

This application is the National Phase of International ApplicationPCT/GB00/01338 filed Apr. 10, 2000 which designated the U.S. and thatInternational Application

FIELD OF THE INVENTION

This invention concerns the preparation of (−)-norlabdane oxide, thefull chemical name of which is1,2,3a,4,5,5a,6,7,8,9,9a,9b-dodecahydro-3a,6,6,9a-tetramethylnaphtho-(2,1-b)-furan.For simplicity this material will generally be referred to herein asnorlabdane oxide.

BACKGROUND TO THE INVENTION

Norlabdane oxide may be structurally shown by structure (1) as follows:

Norlabdane oxide is a well known fragrance material, which is widelyused for providing ambergris-type odours to perfumes. Ambergris is ametabolic product of blue sperm whales which has been used in the pastas a valuable constituent of fine fragrances. Natural ambergris itselfis no longer used for this purpose. However, there is a demand forperfume ingredients with ambergris-type odours. Norlabdane oxiderepresents one of the preferred synthetic compounds with desirableambergris-type odour and is commercially available under various tradenames (notably as Amberlyn, Ambroxan, Ambrox or Amberoxide).

A number of synthetic procedures for norlabdane oxide have beenpublished. Many of these procedures use naturally occurring(−)-sclareol, which may be structurally shown by structure (2) asfollows:

as the starting material from which norlabdane oxide is obtained in amulti-step synthesis.

U.S. Pat. Nos. 5,463,089 and 5,473,085 describe the conversion ofsclareol by use of osmium tetroxide or ozonolysis to an epimeric mixtureof methyl-ketone intermediates 12-acetyl-norlabdane oxide which may bestructurally shown by structures (3a) and (3b) as follows:

Structures (3a) and (3b) may both be represented by structure (3) asfollows:

The 12-acetyl norlabdane oxide of structure (3) is then converted byBaeyer-Villiger oxidation with m-chloroperbenzoic acid in sodium acetatebuffer to an epimeric mixture of the acetates 12-acetoxy-norlabdaneoxide which may be structurally shown by structures (4a) and (4b) asfollows:

Structures (4a) and (4b) may both be represented by structure (4) asfollows:

The 12-acetoxy-norlabdane oxide of structure 4 is then reduced tonorlabdane oxide of structure (1) by use of LiAlH₄/BF₃.OEt₂.

EP 0822191A describes a generally similar conversion of sclareol tonorlabdane oxide, but in which sclareol is converted to12-acetyl-norlabdane oxide via sclareol oxide. The structure of sclareoloxide may be shown by structure (5) as follows:

Sclareol is oxidised with ozone, followed by treatment with alkalinehydrogen peroxide to give sclareol oxide. The sclareol oxide is thenoxidised with an organic hydroperoxide, preferably tert-butylhydroperoxide, to give 12-acetyl-norlabdane oxide. The12-acetyl-norlabdane oxide is converted to 12-acetoxy-norlabdane oxideby oxidation with an organic peracid, preferably peracetic acid. The12-acetoxy-norlabdane oxide is then reduced to norlabdane oxide withsodium borohydride in the presence of a transition metal salt. Thereaction scheme of EP 0882191A may be represented as follows:

The present invention is based on an alternative, novel approach toconversion of 12-acetoxy-norlabdane oxide to norlabdane oxide in placeof the complex metal hydride reduction of the prior art as discussedabove.

SUMMARY OF THE INVENTION

According to the invention there is provided a process for preparing(−)-norlabdane oxide from 12-acetoxy-norlabdane oxide, comprisingsubjecting 12-acetoxy-norlabdane oxide to a hydrogenation reaction toproduce (−)-norlabdane oxide.

Compared with the complex metal hydride reduction of12-acetoxy-norlabdane oxide of the prior art, use of a hydrogenationreaction can have the advantages of reduced effluent and lower cost.

The hydrogenation reaction is conveniently carried out using ahydrogenation catalyst, preferably a noble metal catalyst such as aplatinum catalyst. Good results in terms of reactivity and selectivityhave been obtained using a platinum/zirconium oxide catalyst, preferably5% platinum/zirconium oxide catalyst.

The hydrogenation reaction may be carried out in any suitable solvent,particularly inert hydrocarbon solvents such as octane, hexane, decane,cyclohexane, etc, with cyclohexane currently being favoured.

The reaction may be shown as follows:

The process of the invention may be carried out using one or both of theepimeric forms of 12-acetoxy-norlabdane oxide, ie pure epimer or anepimeric mixture.

The 12-acetoxy-norlabdane oxide is conveniently prepared as described inEP 0822191A, as discussed above. This involves conversion of sclareoloxide to 12-acetyl-norlabdane oxide by oxidation with an organichydroperoxide, preferably tert-butyl hydroperoxide, followed byconversion of 12-acetyl-norlabdane oxide to 12-acetoxy-norlabdane oxideby oxidation with an organic peracid, preferably peracetic acid. Thisprocess produces the 12-acetoxy-norlabdane oxide in the form of anepimeric mixture, which may be used without requiring purification.

The 12-acetoxy-norlabdane oxide may alternatively be prepared by otherknown techniques, for example as described in U.S. Pat. Nos. 5,463,089and 5,473,085.

The invention will be further described, by way of illustration, in thefollowing example.

EXAMPLE

12-acetoxy-norlabdane oxide was prepared as described in EP 0822191A,and the resulting epimeric mixture was used without purification. The12-acetoxy-norlabdane oxide (2.09 g, 7.10 mmol) was mixed with catalystin the form of 5% platinum on zirconium oxide (0.2777 g, 0.07 mmol) exJohnson Matthey, batch 96256, order 56740 in a 50 ml Parr Vessel, and 25mL of cyclohexane was added. The Parr Vessel was fitted into a ParrBench Top Microreactor series 4590, and was flushed with nitrogen gasfor 2 minutes and then flushed with hydrogen gas. The reactor was thenpressurised to 100 bar hydrogen pressure and heated up to 90° C. Thehydrogenation was continued at 90° C. at 80-100 bar hydrogen pressure.The reaction was followed by GC and found to be completed in 20.5 hours.The catalyst of the reaction mixture was then filtered and the productwas analysed by GC. Norlabdane oxide was identified by NMR and IRspectroscopy as the major product, together with a number of sideproducts identified by GCMS. The structures of the various products areillustrated below, with product distribution in % rpa as identified byGC.

GC Method

Hewlett Packard HP 6890 GC system

Column: Model. No. HP 19091J-412

HP-5 5% PhenylMethylsiloxane Capillary

30.0 mX320 μmX0.25 μm nominal

Temp. Program: 100° C., hold 1 minute, ramp 4° C./min., 280° C., hold 2minutes

Analytical Methods

NMR: Jeol GSX 400 NMR

Infra-Red Spectroscopy: ATI Mattson Galaxy 5020FTIR

Norlabdane oxide may be separated from the mixture by columnchromatography for example, for fragrance use.

The best yields of norlabdane oxide have so far been produced using acatalyst of 5% platinum on a zirconium oxide support, as described inthe Example above. Experiments using alternative hydrogenation catalystshave shown that reactivity and selectivity can be substantially affectedby varying the metal loading of the catalyst, changing the metal and/orchanging the support. Platinum catalysts were generally found to be mostactive and selective. Many of the other catalysts tested were found tobe either inactive or not selective in producing norlabdane oxide,producing either no norlabdane oxide or only small amounts of norlabdaneoxide together with other reaction products.

What is claimed is:
 1. A process for preparing (−)-norlabdane oxide from12-acetoxy-norlabdane oxide, comprising hydrogenation of12-acetoxy-norlabdane oxide to produce (−)-norlabdane oxide.
 2. Aprocess according to claim 1, wherein the hydrogenation reaction iscarried out using a hydrogenation catalyst.
 3. A process according toclaim 2, wherein the catalyst comprises a noble metal catalyst.
 4. Aprocess according to claim 3, wherein the catalyst comprises a platinumcatalyst.
 5. A process according to claim 4, wherein the catalystcomprises a platinum/zirconium oxide catalyst.
 6. A process according toclaim 5, wherein the catalyst comprises a 5% platinum/zirconium oxidecatalyst.
 7. A process according to any one of the preceding claims,wherein the hydrogenation reaction is carried out using an inerthydrocarbon solvent.
 8. A process according to claim 7, wherein thehydrogenation reaction is carried out using a solvent selected fromoctane, hexane, decane and cyclohexane.
 9. A process according to claim8, wherein the hydrogenation reaction is carried out using cyclohexanesolvent.
 10. A process according to any one of the preceding claims,wherein the 12-acetoxy-norlabdane oxide comprises one or both of theepimeric forms thereof.
 11. A process according to any one of thepreceding claims, wherein the 12-acetoxy-norlabdane oxide is prepared byoxidation of 12-acetyl-norlabdane oxide with an organic peracid.
 12. Aprocess according to claim 11, wherein the 12-acetyl-norlabdane oxide isprepared by oxidation of sclareol oxide with an organic hydroperoxide.